Method of treatment of emesis and nervous tension in mammals with certain indoles-2-carboxamides and derivatives thereof

ABSTRACT

EMESIS AND/OR NERVOUS TENSION IN MAMMALS ARE SUBSTANTIALLY DIMINISHED BY ADMINSTRATION OF CERTAIN N-(1ALKYL-2-PYRROLIDYLMETHYL)-3-ALKOXY (OR HYDROXY)-INDOLES2-CARBOXAMIDES. TREATMENT MAY BE GIVEN ORALLY OR PARENTERALLY.

United States Patent 3,662,070 METHOD OF TREATMENT OF EMESIS AND NERVOUSTENSION IN MAMMALS WITH CERTAIN INDOLES-Z-CARBOXAMIDES AND DERIVATIVESTHEREOF Michel Leon Thominet, Paris, France, assignor to Societe dEtudesScientifiques et Industrielles de LIle-De- France, Paris, France NoDrawing. Continuation-impart of application Ser. No. 657,010, July 31,1967, now Patent No. 3,573,325, dated Mar. 30, 1971. This applicationJan. 6, 1971, Ser. No. 104,500 Claims priority, application France, July29, 1966, 72,905; Oct. 18, 1966, 80,482 Int. Cl. A61k 27/00 U.S. Cl.424-274 8 Claims ABSTRACT OF THE DISCLOSURE Emesis and/or nervoustension in mammals are substantially diminished by administration ofcertain N-(lalkyl-2-pyrrolidylmethyl)-3-alkoxy (or hydroxy)-indoles-2-carboxamides. Treatment may be given orally or parenterally.

This application is a continuation-in-part of patent application Ser.No. 657,010, filed July 31, 1967, now US. Pat. No. 3,573,325. Thisinvention relates to the treatment of nervous tension and emesis inmammals by the administration of certain new N-(l-alkyl-2-pyrrolidylmethyl)-3- alkoxy (orhydroxy)-indoles-2-carboxamides, their pharmaceutically acceptable acidaddition salts, N-oxide and quaternary ammonium salts. The componentspossess significant therapeutic properties and may be used for thetreatment in mammals of nervous tension and emesis associated with manyconditions, such as pregnancy and seasickness.

The compounds of this invention employed in the therapeutic treatment ofthis invention are N-(1-alkyl-2- pyrrolidylmethyl)-3-alkoxy (orhydroxy)-indole-2-carboxamides, their corresponding pharmaceuticallyacceptable salts of addition with an aliphatic or aromatic acid, N-oxide and quaternary ammonium salts. The N-(1-alkyl-2-pyrrolidylmethyl)-3-alkoxy (or hydroxy)-indole-2-carboxamides have theformula:

HzC-CH2 Y- CONH-CHzH H2 N l I N z R I in which W, X, Y and Z arehydrogen or a halogen such as Cl, Br, F, or a branched or unbranchedalkoxy radical of low molecular weight (from 1 to carbon atoms), atleast two of the substituents of W, X, Y and Z being hydrogen; A and Rare hydrogen or branched or unbranched alkyl radicals of low molecularweight (from 1 to 5 carbon atoms); and R is an alkyl radical of 1 to 2carbon atoms. The substituents of W, X, Y and Z may be in 4 and 5; 4 and6; 4 and 7; 5 and 6; 5 and 7; and 6 and 7.

The process for preparing these compounds utilized in the methods ofthis invention comprises starting either with a lower alkyl-3-alkoxy (orhydroxy)-indole-2-car- 3,662,070 Patented May 9, 1972 "ice boxylate andtreating it with an N-(l-alkyl-Z-pyrrolidylmethyl)-amine so as toproduce the corresponding indole carboxamide, 3-alkoxy (orhydroxy)-indole-2-carboxylic acid 1,l'-sulphinyl diimidazole (Angew.Chem, 7326, 435 (1964)) or 1,1'-carbonyl diimidazole (J. Am. Chem. $00.,82, 4596 (1966)) in order to produce the corresponding N-acyl imidazolewhich gives the corresponding indole carboxamide by reaction with anN-(l-alkyl-Z-pyrrolidylmethyl) -amine.

Typical compounds utilized in the methods of the invention may beproduced as follows.

EXAMPLE I N-( l-ethyl-2-pyrrolidylmethyl) -3 -methoxy-indole-2-carboxamide Phase A: Methyl ester of N-(2-carbomethoxyphenyl)-glycine-In a one liter round-bottomed flask provided with a sealedagitator, a reflux condenser and a thermometer there are introduced 109g. (1 mole) of methyl anthranilate, 302 g. (2 moles) of methylchloroacetate and 140 g. (1 mole) of potassium carbonate. This is heatedat C. for 154 hours.

There is then observed in the bottom of the flask a precipitate ofmineral salts beneath a viscous ester precipitate. 1 liter of water isadded to dissolve the mineral salts and the aqueous solution obtained isdecanted. The viscous residue comprising a mixture of startinganthranilate and ester produced is dissolved with agitation by 250 ml.of water and 200 ml. of concentrated hydrochloric acid. The excess ofanthranilate is dissolved and the ester crystallizes. It is dried,Washed with 200 ml. of 1% hydrochloric acid and 500 ml. of water.

The product obtained is immediately re-diluted in 60 ml. of alcohol,dried, washed with 60 ml. of 95 alcohol and dried at 40 C.

148 g. (yield: 66%) of methyl ester of N-(Z-carbomethoxyphenyl)-glycine(melting point: 95 to 96 C.) are obtained.

Phase B: Methyl indoxylate,-23 g. (1 mole) of sodium are rapidlydissolved in 630 ml. of methyl alcohol in a 2 liter round-bottomed flaskprovided with a reflux condenser, cooling when the reaction is tooquick. 224 g. (1 mole) of methyl ester ofN-(2-carbomethoxyphenyl)-glycine are added and the mixture is heated ina Water bath. The precipitate is completely dissolved in 20 minutes.

After 2 hours, the indoxylate sodium derivative slowly precipitates. Itis heated under strong reflux for 10 hours. After cooling it isdissolved by 4.5 liters of water. There remains an insoluble which isleft to crystallize and is then filtered.

The methyl indoxylate is then precipitated by acetic acid. It is driedwithout heating, washed in water and dried at 40 C.

153 g. of the product are obtained (yield: 80%) (melting point: 157 C.).

Phase C: Methyl 3-methoxy-indole-2-carboxylate.85 g. (0.445 mole) ofmethyl indoxylate, 500 ml. of acetone and 59 g. (0.445 mole+5% excess)of methyl sulfate are introduced into a 2 liter round-bottomed flaskprovided with a sealed agitator, a condenser and a thermometer, and arethen heated at 40 C. 61 g. (0.445 mole) of potassium carbonate areslowly added at one time. Heating under reflux is maintained for 3hours.

350 to 400 ml. of acetone are distilled while agitation continues. It iscooled and 1500 ml. of water are added.

The methyl-3-methoxy-indole-2-carboxylate precipitates. It is driedwithout heating, washed with 120 ml. of soda, 350 ml. of water, anddried.

88 g. of the product are obtained (yield: 97%) (melting point: 107 C.).

Phase D:N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxyindole-2-carboxa1nide.75 g.(0.365 mole) of methyl-3- methoxy-indole-Z-carboxylate, 130 ml. of dryxylene and 95 g. (0.365 mole x 2) of thel-ethyl-Z-aminomethylpyrrolidine are introduced into a 500 ml.round-bottomed flask provided with a 30 cm. Vigreux column. This gentlyheated so as to distill very slowly the methanolxylene azeotrope whichpasses at 63 to 64 C.

The reaction lasts 3 hours 30 minutes. All the methanol produced hasthen been distilled. The temperature rises to 135 C. and a little moreis distilled at this temperature. It is cooled and dissolved with 500ml. of water and 100 ml. of concentrated hydrochloric acid (to aciditywith Congo red). Two layers of liquid are obtained.

The layer of xylene is decanted and extracted once more with 100 m1. ofwater and 10 ml. of concentrated hydrochloric acid.

The combined aqueous solutions are filtered with 2 g. of black and theN-(1-ethyl-2-pyrrolidylmethyl)-3-methoxyindole-2-carboxamide isprecipitated by 105 ml. of ammonia. The precipitate, at first viscous,solidifies. It is dried without heating and washed in water until the Clions disappear. The solid product is recrystallized in a heated state in300 ml. of isopropyl alcohol. It is left to cool, is filtered and washedon a filter with 70 ml. of isopropyl alcohol.

82 g. of the product are obtained (yield: 74%) (melting point: 143 to144 0.).

EXAMPLE II N-( 1-ethy1-2-pyrrolidylmethyl -3-methoxy-indolc-2-carboxamide Phase A: Like Phase A in Example 1.

Phase B: Methyl ester of N-(2-carbomethoxy-4-chlorophenyl)-glycine.89 g.(0.4 mole) of methyl ester of N- (2-carbomethoxyphenyl)-glycine and 500ml. of acetic acid are introduced into a 1 liter round-bottomed flaskprovided with an agitator and a. thermometer, and are heated to 40 C. todissolve everything. The solution is then cooled to 27 C. and 53.5 g.(0.4 mole) of chlorosuccinimide are introduced in portions between andC. The solution is then agitated for 4 hours 30 minutes at 2530 C. andthen left to react at 30 C. for 40 hours. Only traces ofchlorosuccinimide are left in solution.

The solution produced is poured into 5 liters of water. TheN-(2-carbomethoxy-4-chlorophenyl)-glycine methyl ester formedprecipitates. It is dried without heating, washed in water and dried atC.

95 g. of this product are obtained (yield: 92%) (melting point: 100-104C.).

Phase C: Methyl-5-chloroindoxylate.-9.5 g. (0.415 mole) of sodium aredissolved in 190 ml. of methyl alcohol in a 1 liter round-bottomed flaskprovided with a reflux condenser, N-(2-carbomethoxy-4-chlorophenyl)-glycine is added and the flask is put on a boiling water bath. Thesodium derivative begins to precipitate. before the ester is totallydissolved. Heating continues for 10 hours. It is cooled and then dilutedwith 1700 ml. of water. A fairly large insoluble amount remains which isfiltered with 3 g. of black. The methyl-5-chloroindoxylate is thenprecipitated by 70 ml. of acetic acid. It is dried without heating,washed in water and dried. The product obtained is re-dissolved in acold state in 800 ml. of water and 29 ml. of soda lye. There stillremains an insoluble which is filtered and washed. Themethyl-S-chloroindoxyL ate is precipitated by 60 ml. of acetic acid. Itis dried without heating, washed in Water and dried.

g. of this product are obtained (yield: 62%) (melting point: 202 to 203C.).

Phase D: Methyl-3-methoxy-5-chloroindole-Z-carboxylate.43 g. (0.19 mole)of methyl-5-chloroindoxylate, 310 ml. of acetone and 25 g. (0.19 mole+4%excess) of methyl sulfate are introduced into a 1 liter round-bottomedflask provided with a sealed agitator, a reflux condenser, a thermometerand a dropping funnel, and are heated to 40 C. Only part of theindoxylate dissolves. 26 g. (0.19 mole) of potassium carbonate are thenadded in a single portion in a thin stream and heating under reflux iseffected for 3 hours 30 minutes. A part of the acetone (250 ml.approximately) is then distilled, cooled and diluted with 350 ml. ofwater. The methyl-3-methoxy-5-chloroindole- 2-carboxylate precipitates.It is dried without heating, washed with ml. of 2% soda and then withwater and dried.

45 g. of this product are obtained (yield: 99%) (melting point: 144 C.).

Phase E: N- 1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-chloroindole-2-carboxamide.33 g. of methyl-3-methoxy-S-chloroindole-Z-carboxylate, 57 ml. of xylene and 35 g. ofl-ethyl-2-aminomethyl pyrrolidine are introduced into a 250 ml.round-bottomed flask provided with a Vigreux column, and are gentlyheated in order to distill the methanol-xylene azeotrope which passes at64 C. After 3 hours 30 minutes to 4 hours all the methanol hasdistilled. A little more xylene is distilled.

It is then cooled, dissolved with 400 ml. of water and 40 ml. ofconcentrated hydrochloric acid. The hydrochloride which is littlesoluble in cold water, crystallizes. The xylene must therefore be washedaway in water. The solution obtained is filtered while boiling with 2 g.of black and the base is precipitated in a hot state by 48 ml. ofammonia. At first viscous, the base solidifies. It is then dried withoutheating, washed in water and dried.

The base obtained is re-dissolved in 500 ml. of water and 22 ml. ofconcentrated hydrochloric acid. The solution is treated with 5 ml. ofsodium bisulphite for several hours. When the hydrochloride hasrecrystallized, the solution is heated and filtered while boiling with 2g. of black and the base is then precipitated by 35 ml. of ammonia. Theprecipitate which is at first viscous solidifies. After cooling it isdried without heating and washed in water until the chlorine ionsdisappear.

34 g. of 3-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-chloroindole-2-carboxamide are obtained (yield: 74%) (melting point: 178to 179 C.).

Phase F: N-(1-ethyl-2-pyrrolidylmethyl)-3-methoxy-5-chloroindole-2-carboxamide hydrochloride-34 g. (0.1 mole) of N (1ethyl-2-pyrrolidylmethyl)-3-methoxy-5- chloroindole-Z-carboxamide aredissolved in ml. of methyl alcohol and 3.6 g. of dry hydrochloric aciddissolved in 50 ml. of methyl alcohol are added. The indolehydrochloride formed precipitates. It is dried without heating, washedon a filter with 30 ml. of methyl alcohol and then 30 ml. of acetone andis dried. It is a solid white body: melting point: 229 to 233 C.

EXAMPLE III N- l-ethyl-2-pyrrolidylmethyl)-1-methy1-3-methoxyindole-2-carboxamide Phase A: N-methylanthranilic acid-137 g. (1mole) of :anthranilic acid and 400 ml. of water are introduced into a 2liter round-bottomed flask provided with an agitator, a thermometer anda dropping funnel, and 101 ml. of soda lye are added untilphenolphthalein changes color. The solution obtained is heated to 32 C.and 126 g. (1 mole) of methyl sulfate are added drop by drop. Thereaction is exothermic and cooling is effected if necessary in order notto exceed 45 C. N-methylanthranilic acid precipitates from the beginningof the reaction. When addition is completed, agitation is continued for1 hour more. The solution is then cooled, dried without heating andwashed in water until the sulfate ions are eliminated. The acid obtainedis recrystallized in 115 ml. of acetic acid. After cooling. it is driedwithout heating, washed with 10 ml. of acetic acid and then in water anddried.

91 g. of N-methylanthranilic acid are obtained (yield: 80%) (meltingpoint: 176 to 177 C.).

Phase B: N-methyl-N-(Z-carboxyphenyl)-glycine.9l g. (0.60 mole) ofN-methylanthranilic acid, 260 ml. of water and 61 ml. of soda areintroduced in a 2 liter roundbottomed flask provided with a refluxcondenser until phenolphthalein changes color. In a separate flask 85 g.(0.60 mole+% excess) of monochloroacetic acid are dissolved in 180 ml.of water and 48 g. of sodium carbonate, and the two solutions are mixed.They are heated under reflux for 6 hours 30 minutes. The solutionobtained is cooled, filtered with 2 g. of black and acidified with 50ml. of concentrated hydrochloric acid. The acid precipitates after adelay. It is dried without heating and washed in water until thechlorine ions are eliminated and dried at 40 C.

This acid is recrystallized in 250 ml. of acetic acid. After cooling itis dried without heating, washed in acetic acid and then in water anddried at 40 C.

71 g. of N methyl-N-(2-carboxyphenyl)-glycine are obtained (yield: 84%)(melting point: 190 to 191 C.).

Phase C: N-methyl-N-(Z-carbomethoxyphenyl)-glycine methyl ester.--395ml. of methyl alcohol, and then drop by drop with cooling 170 g. of 20%S0 oleum, and finally 110 g. of N-methyl-N-(2-carboxy-phenyl) glycineare introduced into a 1 liter round-bottomed flask provided with areflux condenser. Heating under reflux is eflected for hours. A part ofthe alcohol (150 ml.) is then distilled and the residue is poured into asolution of 200 g. of sodium carbonate in 2 liters of water. The esterseparates in the form of an oil which is decanted. It is verified thatthe solution is slightly alkaline and it is extracted with ether. Theethereal organic solution is dried on potassium carbonate. After theether is eliminated, the ester is distilled under vacuum.

86 g. (yield: 69%) of N-methyl-N-(2-carbomethoxyphenyl) glycine methylester are obtained (melting point: 172 to 173 0.).

Phase D: Methyl N-methyl indoxylate.8.35 g. of sodium (0.3 63 mole) aredissolved in 230 ml. of methanol in a 500 ml. round-bottomed flaskprovided with a reflux condenser. 86 g. (0.363 mole) of N-methyl-N-(Z-carbomethoxyphenyl) glycine methyl ester is added, and the mixture isheated in a water bath. The indoxylate soda derivative begins toprecipitate from the beginning of the reaction. Heating under reflux iscontinued for 6 hours 30 minutes. The mixture is then cooled and dilutedwith 2300 ml. of water. There remains an insoluble which is filtered andwashed. Ether extraction is then efiected to produce a clear solutionfrom which the indoxylate is precipitated by the addition of aceticacid.

The precipitate obtained is dried without heating, washed in water untilit is neutral and dried at 40 C. (melting point: 148 C.) (yield: 77%).

Phase E: Methyl 1 methyl-S-methoxy-indole-Z-carboxylate.-57 g. (0.278mole) of methyl N-methyl indoxylate, 400 ml. of acetone and 38 g. (0.278mole+1% excess) of dimethylic sulfate are introduced into a 500 ml.round-bottomed flask provided with a sealed agitator, a reflux condenserand a thermometer, and heated to 40 C. 38 g. (0.278 mole) of potassiumcarbonate are then added slowly in a single portion. It is then putunder reflux for 3 hours.

150 ml. of acetone is distilled and dissolved with 1.600 liters ofwater. The methyl ester crystallizes after a delay. It is dried withoutheating, washed in water and dried in air (melting point: 42 to 43 C.)(Weight 57 g.) (yield: 94%

Phase F: 1 methyl 3 methoxyindole-2-carboxylic acid.57 g. (0.26 mole) ofmethyl-1-methyl-3-methoxyindole-Z-carboxylate, 73 ml. of alcohol and 27ml. of 30% soda are introduced into a 500 ml. round-bottomed flaskprovided with a reflux condenser and are heated in a water 6 bath. Thesodium salt precipitates immediately and sets in a mass.

After 1 hour 30 minutes to 2 hours of reflux, 250 ml. of water aregradually added, heating being maintained. The sodium salt dissolves. Itis then diluted with 500 ml. of water, and the solution is cooled andfiltered with 1 g. of black. The acid is then precipitated by 29 ml. ofconcentrated hydrochloric acid. After cooling it is dried withoutheating, washed in water until the chlorine ions are eliminated and isthen dried at 40 C.

51 g. (yield: 95%) of 1-methyl-3-methoxyindole-2- carboxylic acid isobtained (melting point: 109 to 110 0).

Phase G: N-(l ethyl-2-pyrrolidylmethyl)-1-methyl-3-methoxyindole-Z-carboxamide.--84 g. (0.245 mole x 5) of imidazole aredissolved in 540 ml. of tetrahydrofuran in a 2 liter round-bottomedflask provided with a sealed agitator, a reflux condenser, a thermometerand a dropping funnel. 37 g. of thionyl chloride are poured in withoutexceeding 10 C. Imidazole hydrochloride precipitates from the beginningof the reaction. The temperature is subsequently allowed to rise to 20C. and is maintained for half an hour.

51 g. (0.245 mole) of finely powdered l-methyl-3-methoxyindole-Z-carboxylic acid is added. A change in the appearance ofthe precipitate is observed at the same time as a rise in temperature.After cooling to 20 C., the mixture is maintained for 1 hour 15 minutesat 50 C.

The mixture is cooled to 20 C. and 50 g. of triethylamine is added. Thetemperature again rises to 33 C. and the precipitate again changes inappearance. The mixture is heated to 50 C. and maintained for 45minutes. After cooling to 20 C., 63 g. (0.245 mole x 2) of 1-ethyI-Z-aminomethyl pyrrolidine is poured in drop by drop. Thetemperature rises to 35 C. The mixture is maintained for 1 hour at thistemperature and then for 2 hours 30 minutes at 50 C.

The precipitate is then dried without heating and washed with 150 ml. oftetrahydrofuran. The major part of the solvent is distilled undervacuum. The residue is dissolved in 520 ml. of water. The base isprecipitated in part. Precipitation is completed by adding ml. ofammonia. The base obtained is liquid. It is decanted and extracted withether. The ethereal layer is dissolved With 500 ml. of water and 50 ml.of concentrated hydrochloric acid. The ether is decanted and washed oncewith acid Water. The aqueous solutions are brought together. The pH isrestored to 6. The solution obtained is treated with 7 ml. of sodiumbisulphite. Considerable discoloration is observed. The base is againprecipitated by adding ml. of ammonia. It is decanted, the aqueoussolution is extracted with ether and the ethereal solution is washedthree times with ml. of Water. It is then dried on potassium carbonate.The ether is then distilled, concluding under vacuum, until a constantweight is attained.

83 g. (yield: 96.5%) ofN-(1-ethyl-2-pyrrolidylmethyl)-l-methyl-3-methoxyindole-2-carboxamide isobtained.

Phase H: N-(1-ethyl-2-pyrrolidylmethyl)-1-methyl-3-methoxyindole-2-carboxamide phosphate.The base obtained in Phase G isdissolved in 300 ml. of absolute alcohol and 35 g. of 85% phosphoricacid dissolved in 40 ml. of alcohol is then added. The phosphatecrystallizes, is dried without heating, washed in alcohol and dried at40 C. (melting point: 164 (3.).

EXAMPLE IV N-( 1-ethyl-2-pyrrolidylmethyl) -1-ethyl-3-methoxyindole-2-carboxamide Phase A: N-ethyl-anthranilic acid-247 g. (2 moles) ofanthranilic acid and 800 ml. of water are introduced into a 3 literround-bottomed flask provided with an agitator, a thermometer and adropping funnel, and 200 ml. of 30% soda is added until phenolphthaleinchanges color. The solution obtained is heated at 35 to 40 C. and

7 308 g. (2 moles) of ethyl sulfate are added drop by drop. TheN-ethyl-anthranilic acid precipitates from the beginning of the additionwhich lasts approximately 1 hour 15 minutes. The reaction is exothermicand is slightly cooled in order that the temperature does not exceed 48to 49 C.

Agitation is then maintained for 1 hour. After cooling, the precipitateis then dried without heating, washed in water until the sulfate ionsare eliminated and is then dried.

277 g. (yield: 84%) of N-ethyl-anthranilic acid is obtained (meltingpoint: 154 C.).

Phase B: N-ethyl-N-(2-carboxphenyl) glycine.183 g. (1.11 mole) ofN-ethyl anthranilic acid, 457 ml. of water and 110 ml. of 10% soda areintroduced into a 2 liter round-bottomed flask provided with a refluxcondenser, until phenolphthalein changes color. In another flask 157 g.(1.11 mole+50% excess) of monochloroacetic acid is dissolved in 350 ml.of water and 89 g. of sodium carbonate, and the two solutions are mixed.Heating under reflux is effected for 4 hours. The solution obtained isfiltered with 2 g. of black and then acidified with 90 ml. ofconcentrated hydrochloric acid until Congo red changes color. The acidoccasionally precipitates after a delay. It is dried Without heating,washed in water until the chlorine ions are eliminated and is dried at40 C.

180 g. (yield: 73%) of N-ethyl-N-(Z-carboxyphenyl)- glycine is obtained(melting point: 190 to 191 C.).

Phase C: N-ethyl-N-(2-carbomethoxyphenyl)glycine methyl ester.-300 ml.of methyl alcohol is introduced into a 1 liter round-bottomed flaskprovided with a reflux condenser, and then drop by drop and with cooling160 g. of 20% oleum and finally 90 g. (0.4 mole) of N-ethyl-N-(2-carboxyphenyl) glycine which dissolves rapidly.

Heating under reflux is effected for 10 hours. A part of the alcohol isthen distilled and the residue is poured into a solution of 180 g. ofsodium carbonate in 2 liters of water. The ester separates in the formof an oil which is decanted. It is verified that the aqueous solution isslightly alkaline and it is extracted with ether. The ethereal organicsolution is dried on potassium carbonate. After the ether is eliminated,the ester is distilled under vacuum (B.P./5 mm.: 156 to 157 C.) (weight:62 g.).

Phase D: Methyl-N-ethyl indoxylate.-5.7 g. (0.247 mole) of sodium isdissolved in 110 ml. of methanol in a 500 ml. round-bottomed flaskprovided with a reflux condenser. 62 g. (0.247 mole) ofN-ethyl-N-(Z-carbomethoxyphenyl) glycine methyl ester is added and themixture is heated in a boiling water bath. A fluorescent solution isobtained which is heated under reflux for 6 hours 30 minutes.

The solution is cooled and diluted with 1 liter of water. There remainsan insoluble which gradually solidifies. The solution which was stillslightly cloudy is filtered and extracted with ether.

The indoxylate is then precipitated by adding 40 ml. of acetic acid. Theprecipitate is dried wthout heatng, washed in water until it is neutraland dried at 40 C. (Weight: 42 g.) (melting point: 88 to 89 C.).

Phase E: Methyl-l-ethyl-3-methoxyindole-2 carboxylate.43 g. (0.19 mole)of methyl-N-ethyl indoxylate, 210 m1. of acetone and 25 g. of methylsulfate are introduced into a. 1 liter round-bottomed flask providedwith a sealed agitator, a reflux condenser and a thermometer, and themixture is heated to 40 C. A solution is obtained to which 26 g. ofpotassium carbonate is added slowly and in a single portion. Thereaction is slightly exothermic and the temperature rises from 4 to 5 C.The solution is then heated under reflux for 3 hours.

190 ml. of acetone is then distilled, and the residue is cooled anddissolved with 200 ml. of water. The mineral salts dissolve and themethyl derivative which is at first liquid solidifies. It is driedwithout heating, washed with 120 ml. of 2% soda and then in water, andis dried.

43 g. of this product is obtained (yield: 98%) (melting point: 57 C.).

Phase F: 1-ethyl-3-rnethoxyindole-2-carboxylic acid. 47 g. (0.18 mole)of methyl-1-ethyl-3-methoxyindole carboxylate, 55 ml. of ethyl alcoholand 20 ml. of 30% soda are introduced into a 500 ml. round-bottomedflask provided with a reflux condenser, and the mixture is then heatedon a water bath. The sodium salt precipitates very rapidly, and sets ina mass. After 1 hour 30 minutes 100 ml. of water is gradually added,heating being maintained. The solution is then diluted with 400 ml. ofwater, and the solution obtained is slightly cooled and filtered with 1g. of black.

The acid is then precipitated by adding 20 ml. of concentratedhydrochloric acid to the luke warm solution. At first liquid, itsolidifies. After cooling, it is dried without heating, washed in wateruntil the chlorine ions are eliminated and is dried at 40 C.

37 g. (95%) of a product melting at 102 C. is obtained.

Phase G: N (1-ethyl-2-pyrrolidylmethyl)-1-ethyl-3-methoxyindole-2-carboxamide.136 g. (0.4 mole x 5) of imidazole isdissolved in 800 ml. of tetrahydrofuran in a 2 liter round-bottomedflask provided with a sealed agitator, a reflux condenser and athermometer, and 61 g. of thionyl chloride is introduced drop by dropwithout exceeding 10 C. Imidazole hydrochloride precipitates from thebeginning of the reaction. Agitation is subsequently maintained for halfan hour at 20 C. 88 g. (0.4 mole) of finely powdered1-ethyl-3-methoxyindole- 2-carboxylic acid is then added. Thetemperature rises to 32 C. at the same time as the precipitateliquefies. It is cooled to 20 C., this temperature being maintained for1 hour, and is then heated at 50 C. for 30 minutes.

The solution is cooled to 20 C. and 81 g. (0.4 mole x 2) of1-ethyl-2-aminomethyl-pyrrolidine is added drop by drop. The reaction isexothermic. The temperature attains 38 C. In this condition agitation iseffected for 1 hour and then for 2 hours at 50 C.

After cooling, the precipitate is dried without heating and washed with300 ml. of tetrahydrofuran. The major part of the solvent is thendistilled under vacuum. The residue is dissolved in 1 liter of water andthe pH is brought to approximately 6 by adding ml. of concentratedhydrochloric acid. The solution obtained is treated with 10 ml. ofsodium bisulfite for 1 hour 30 minutes and is filtered with 2 g. ofblack. The ethereal solution obtained is washed six times with 100 ml.of Water and dried on potassium carbonate. The ether is then distilled,concluding under vacuum, until a constant weight is obtained.

126' g. (yield: 96%) of N-(1-ethyl-2-pyrrolidylmethyl)-1-ethyl3-methoxyindole-2-carboxamide is obtained.

Phase H: N (1-ethyl-2-pyrrolidylmethyl)-1-ethyl-3-methoxyindole-Z-carboxamide phosphate.The base 126 g.) is dissolved in300 ml. of alcohol and 45 g. of 85% phosphoric acid dissolved in 50 ml.of alcohol is added. The phosphate crystallizes slowly after beingstarted. It is dried without heating, washed with 200 ml. of absolutealcohol, first dried in air and then at 40 C.

122 g. (yield: 75%) of product (melting point: to 152 C.) is obtained.

EXAMPLE V N-1-ethyl-2-pyrrolidylmethyl)-1-propyl-3-methoxyindole-Z-carboxamide PhaseA: N-propyl anthranilic acid-205 g. 1.5 moles) of anthranilic acid and600 ml. of water are introduced into a 3 liter round-bottomed flaskprovided with a condenser, and 150 ml. of 30% soda is added. 188 g. (1.5moles) of propyl bromide is then introduced and heating under reflux iseffected for 12 hours. When the reaction is completed, cooling iseffected under agitation, the N- propyl anthranilic acid which is formedsolidifies but remains slightly viscous. It is dried without heating andwashed with a little water.

This precipitate is redissolved in 250 ml. of water and 200 ml. of 30%soda lye. A thin oily layer remains floating on the surface and isfiltered and washed with 100 ml. of water. By cooling the sodium saltcrystallizes. It is dried without heating at about C. and washed with250 ml. of icy cold water. It is immediately redissolved in 1 liter ofhot water. The cloudy solution is filtered and the acid is precipitatedin its hot state by 60 ml. of acetic acid. After cooling, it is driedwithout heating, washed in water and dried at 40 C.

106 g. (yield: 39%) of N-propyl anthranilic acid (melting point: 113 to114 C.) is obtained.

Phase B: N-propyl-N-(Z-carboxyphenyl) glycine.-106 g. (0.59 mole) ofN-propyl anthranilic acid, 240 ml. of water and 62. mol. of 30% soda areintroduced into a 1 liter round-bottomed flask provided with a refluxcondenser. In another flask 84 g. of chloroacetic acid are dissolved in110 ml. of water and 47 g. of sodium carbonate and the two solutions aremixed. Heating under reflux is elfected for 6 hours.

The solution obtained is cloudy and is filtered with 3 g. of black. Asthe sodium salt crystallizes, heating to close to the boiling point mustbe effected in order to dissolve everything. The acid is thenprecipitated by 50 ml. of hydrochloric acid.

After cooling, the N-propyl-N-(2-carboxyphenyl) glycine formed is driedwithout heating, washed in water until the chlorine ions are eliminatedand is dried at 50 C.

101 g. of product are obtained (yield: 72%) (melting point: 205 to 206C.).

Phase C: N-propyl-N-(2-carbomethoxyphenyl) glycine methyl ester.-32 0 g.of methyl alcohol are introduced into a 1 liter round-bottomed flaskprovided with a reflux condenser, and then drop by drop with cooling 168g. of S0 oleum, and finally 99 g. (0.42 mole) of N-propyl-N-(Z-carboxyphenyl)glycine. Heating under reflux is effected for10 hours.

A part of the alcohol is then distilled and the residue is poured into asolution of 168 g. of sodium carbonate in 1500 ml. of water. It isverified that the aqueous solution is slightly alkaline and it isextracted with ether. The ethereal solution is washed with 100 ml. ofwater containing 10 ml. of acetic acid and is then dried on calciumchloride. After the ether is eliminated, the ester is distilled undervacuum.

73 g. (yield: 66%) of N-propyl-N-(2-carbomethoxyphenyl) glycine methylester is obtained: B.P./ 13-14 mm.184'-185 C.

Phase D: Methyl-N-propyl indoxylate.-6 g. (0.275 mole) of sodium isdissolved in 125 ml. of ethyl alcohol in a 500 ml. round-bottomed flaskprovided with a reflux condenser, and 73 g. (0.275 mole) ofN-propyl-N-(Z-carbomethoxyphenyl) glycine methyl ester is added. Asolution is obtained which is heated under reflux in a water bath for 12hours.

The solution is cooled and 1250 ml. of water is added. An insolublewhich is left is filtered. As the solution is still slightly cloudy, itis extracted once with a little ether. The indoxylate is thenprecipitated by ml. of acetic acid. At first liquid, it solidifies whena stream of air is passed through it. It is dried without heating,washed in water until it is neutral and dried in air.

38 g. of this product (yield: 59%) (melting point: 65 to 66 C.) isobtained.

Phase E: Methyl-l-propyl-3-methoxyindole-2-carboxylate.--38 g. ofmethyl-N-propyl indoxylate, 200 ml. of acetone and 22 g. of methylsulfate are introduced into a l-liter round-bottomed flask provided witha sealed agitator, a reflux condenser and a thermometer, and the mixtureis heated to 40 C. A solution is obtained to which 22 g. of potassiumcarbonate is slowly added in a single portion, the solution then beingheated under reflux for 3 hours 30 minutes.

A part of the acetone is distilled, is cooled and 500 ml. of water isadded under agitation. The mineral salts dissolve. The ester separatesin liquid form. It is decanted and the aqueous solution is extractedwith methylene chloride. The organic solution produced in this way iswashed with 3 times 100 ml. of 2% soda and then dried on potassiumcarbonate. The methylene chloride is then distilled.

39 g. (yield: 100%) of methyl-l-propyl-3-methoxyindole-Z-carboxylate isobtained.

Phase F: l-propyl-3-methoxIyindole-2-carboxylic acid. 39 g. (0.16 mole)of methyl-l-propyl-3-methoxyindole- 2-carboxylate, 50 ml. of alcohol and18 ml. of 30% soda are introduced into a 500 ml. round-bottomed flaskprovided with a reflux condenser, and the mixture is heated in a waterbath. The sodium salt precipitates and sets in a mass very rapidly.

After two hours 500 ml. of water are added gradually, heating beingmaintained. The salt dissolves and a cloudy solution is obtained and isthen filtered with 3 g. of black. The acid is then precipitated by 20ml. of hydrochloric acid. After cooling the acid is dried withoutheating, washed in water until the chlorine ions are eliminated anddried at 40 C.

33 g. (yield: 89%) of 1-propyl-3-methoxyindole-2- carboxylic acid isobtained (melting point: 91 to 92 C.).

Phase G: N-(l-ethyl-2-pyrrolidylmethyl)-l-propyl3-methoxyindole-2-carboxamide.85 g. (0.25 mole x 5) of imidazole isdissolved in 520 ml. of tetrahydrofuran in a 2 liter round-bottomedflask provided with a sealed agitator, a reflux condenser and athermometer, and 38 g. of thionyl chloride is poured in without thetemperature exceeding 10 C. Imidazole hydrochloride precipitates fromthe beginning of the reaction. The temperature is then allowed to riseto 20 C. and is maintained for half an hour.

59 g. of finely powdered 1-propyl-3-methoxyindole-2- carboxylic acid isthen added. The temperature rises to 3536 C. and the mixture becomesmore liquid. The mixture is then cooled to 20 C. and then heated at 50C. for 30 minutes. After cooling to 20 C., 51 g. of triethylamine isadded drop by drop. The temperature rises to 34 C. at the same time asthe precipitate again changes in appearance. The temperature ismaintained for 1 hour at 50 C. and then reduced to 20 C. by cooling.

64 g. (0.25 mole x 2) of 1-ethyl-2-aminoethylpyrrolidine is added dropby drop. The temperature rises to 36- 37 C. in 10 minutes. Agitation iseffected at this temperature for 1 hour and then for 3 hours at 50 C.

After cooling, the precipitate is dried without heating and Washed with300 ml. of tetrahydrofuran. The major part of the solvent is distilledunder vacuum. The residue is taken up by 650 ml. of water and dissolvedby adding ml. of concentrated hydrochloric acid, the pH being adjustedto 6-7. The solution is cloudy and is filtered with 2 g. of black. Thebase is then precipitated by 160 m1. of ammonia. It is decanted and theaqueous solution is extracted with ether.

The ethereal solution produced in this manner is dissolved with 500 ml.of water and 50 ml. of concentrated hydrochloric acid. The basedissolves in the water in the form of hydrochloride. The ether isdecanted. The base is again precipitated by adding ml. of ammonia. It isdecanted and the aqueous solution is extracted with ether and theethereal solution is washed three times with ml. of water and is thendried on potassium carbonate. The ether is then distilled.

83 g. (yield: 96.5%) ofN-(1-ethyl-2-pyrrolidylmethyl)-propyl-3-methoxyindole carboxamide isobtained.

Phase H: N-(l-ethyl-2-pyrrolidylmethyl)-l-propyl-3-methoxy-indole-Z-carboxamide phosphate.68 g. (0.2 mole) ofN-(1-ethyl-Z-pyrrolidylmethyl) 1 propyl-3- methoxyindole-Z-carboxamideare dissolved in ml. of absolute alcohol. 25 g. of 85% phosphoric aciddissolved 1 1 in 25 ml. of absolute alcohol are added. The phosphate Thefollowing table shows the result of the testing crystallizes. It isdried without heating and washed in of the compounds employed in themethods of this inalcohol. vention.

73 g. (yield: 83%) of product (melting point: 145- Degree of protectionwith 146 C.) is obtained. Compounds: a dose of 2.5 mg./kg. (base),percent The acute degrees of toxicity which have been studied N-(l-ethyl2 pyrrolidylmethyl) -3-methoxyon mice have shown that the compoundswhich are the tindole-Z-crarboxamide 100 object of the present inventionare of a toxicity which is N-(l-ethyl-Z-pyrrolidylmethyl) 3methoxycompletely compatible with therapeutic use. They have5-chloroindoIe-Z-carboxamide 100 been summed up by way of example in thefollowing N-(l-ethyl 2 pyrrolidylmethyl)-1'methyl-3- table.methoxyiudole-2-carboxamide 100 LD in mg./kg. (CompoundN-(1-ethy1-2-pyrrolidylmethyl) 1 ethyl-3- Compounds: in base form), i.v.methoxyindole-Z-c-arboxamide 100 N-(l-ethyl-2-pyrrolidylmethyl) 3methoxy- N-(l-ethyl-Z-pyrrolidylmethyl) 1 propyl-3- iindole-Z-carboxamide 23.5 methoxyindole-2-carboxamide 100 N-(l-ethyl 2pyrrolidylmethyl)-3-methoxy N-(l-ethyl-Zpyrrolidylmethyll 1 buty1-3-5-chloro-indole-Z-carboxamide 33.4 rnethoxyindole-Z-carboxamide 100 N gggi g gi s iggggg ff??? i 113 The pharmacological effects on the centralnervous sys- N (1 ethy1 2 pynolidylmethyl) 1 ethy1 3 tern of compoundsutilized m the methods of this invention methoxy.mdole-g carboxamide 15Were studled and the ollow ng results are given by way N (1 ethy1 2pyrrolidylmethyl) 1 propy1 3 of example for four such compounds.

mCthOXY-iHdOIC-Z-carboxamide co d 1= 1- m 1.2- rrolid lmeth 1N-(1-ethyl-%-pyrrolidylmethyl)- 1 butyl-3- mjthoxyindoleacarbgxanfige yy 3 methoxy-lndole-Rambo[111de Compound2=N-(l-ethyl-2-pyrrolidylmethyl)-1-methy1 The anti-emetic action ofthese compounds on the 3"mBthOXYiIIdOIB-Z-carboxamide vomiting centershas been studied on dogs by means of Compound 3= y -py y y y apomorphinein accordance with the technique of Chen 3-methoxyindole-2-carboxamideand Ensor taken up by Ducrot and P. Decourt. Tests Compound4=N-(1-ethyl-2-pyrrolidylmethyl)-1-pr0pylwere carried out on groups offour dogs.

3-methoxyindole-2-carboxamide Compound Test 1 2 3 4 Cataleptio activity,EDBO mg./kg./ 0% effect at 20 rug/kg--. 17.2 9.1 2.1.

S.C (has rat. Traction test, EDfiu mg.Ikg./S.C. 20% effect at 60 mg-Ig.--. 23-7 30.8-33.9 5- -315.

(base), mouse. Potentialization of the barbituric Inactive index=0.93 atIndex=1.23 at mgJkg--. Index=1.65 at 40 mgJkg. ##39.

narcosis, EDao mg./kg./i.p. (base), 40 mgJkg.

mouse. Spontaneous motility, ED 0 mg./kg.l

1.p. mouse:

Winter and Flateker test 25.7 6.3 ##25436 A Ac v Lg ar n imorp ine ac ivy, mg. nae ive pro ec ion 1 e ect at 80111 k 31 efiect 0 kg'lplo smouse. at 100 g g u E g at 8 mg [kg 18% effect at 150 mgJkg.Antitremorine activity, EDao mg./ .9 #9 2.8 20% efiect at 30 mg./kg

kg./i.p. (base), mouse. Revolving shaft test, ED50 mgJkgJ 42.8 1 -8 17.724.9.

i.p. (base), mouse. Anti-convulsant activity:

Electrical crisis, 8.0

EDsu mg./kg., mouse, p.0 3oz l7fgplr gtiection at 200 Nil eiiect at 100mg./kg Nil eflect at 100 mg.lkg Nil efiect at 100 mg./kg. Analgesicactivity:

EDS) 20% efiect at 40 effect at 40 mg,/kg 40% efi t t 50 ChemicalStimulus. E1350 e ect at 80 mg-/kg.... ##29 33% fi t at 40% at 40 mgJkg.

kg./i.p., mouse.

The apomorphine was administered subcutaneously in doses of 0.10 mg./kg. The compounds under study were 60 The compounds utilized in themethods of treatment of administered 30 minutes previously, alsosubcutaneously. this invention may be administered parenterally ororally,

The number of vomitings was counted in the 30 minutes desirably aspharmaceutically acceptable salts. They may following the lIljCCtlOD. ofapomorphine. be used in the form, for example, of sugar coated tablets,In the g, g were treated Wlth the compounds injectable solutions inampoules, aqueous solutions for use employed in the methods of thisinvention and further received the apomorphine. Their behavior wascompared with dogs and received apo-morphine only. The vomitings werenumbered in each case. If the dogs treated with the compounds employedin the methods of this invention had vary Wlth he seventy of i emeslsnervous tenslon no vomiting at all, they were deemed protected at 100%.treated. with i t havmg the Weight span of f If theyhad as manyvomitings as the dogs having received the dally dosage 1S m the range of20 to 500 accordmg 65 in aerosol or other sprays, suppositories,granulated preparations with sugar and sweetened syrups.

The duration of the treatment and the dosage utilized apomorphine only,they were deemed protected at 0%. to the weight of the mamnlal andseve'rity of i11ne$$- Between these two extreme values, the proportion fSuch treatment and dosage in a particular situation would vomitings inthe two groups of dogs was calculated, acbe delel'mlned y a ProfessionalSkilled in the aft of the prevention, cure and alleviation of diseases,illness and injury of mammals, guided by the data given herein.

cording to which, the degree of protection between 0 and 100 wasdetermined.

What is claimed is:

1. The method of treating emesis or nervous tension in mammals, saidmethod comprising administering to a mammal requiring such treatment atherapeutically eflective dose of aN-(I-alkyl-2-pyrrolidylmethyl)-3-alkoxy- (orhydroxy)-indole-2-carboxamide, a pharmaceutically acceptable acid saltthereof, an N-oxide thereof or a quaternary salt thereof, saidN-(1-alky1-2-py1'rolidylmethyl)- 3-alkoxy-(orhydroxy)-indole-2-carboxamide having the formula:

I Z R1 in which W, X, Y and Z are hydrogen, halogen or lower alkyl, atleast two of W, X, Y, and Z being hydrogen; A is hydrogen or loweralkyl; R is hydrogen or lower alkyl; and R is methyl or ethyl.

2. The method of claim 1 in which the daily dose is 20 to 500 mg.

3. The method of claim 1 in which the compound is 14 N-(l-ethyl 2pyrrolidylmethyl)-3-methoxyindole-2-can boxamide.

4. The method of claim 1 in which the compound is N-(l ethyl 2pyrrolidylmethyl)-3-methoxy-5-chloroindole-Z-carboxamide.

5. The method of claim 1 in which the compound is N-(l-ethyl 2pyrrolidylmethyl)-1-methyl-3-methoxy-indole-2-carboxamide.

6. The method of claim 1 in which the compound is N-(l ethyl 2pyrrolidylmethyl)-1-ethyl-3-methoxy-indole-2-carboxamide.

7. The method of claim 1 in which the compound is N-(l-ethyl 2pyrrolidylmethyl)-1-propyl-3-methoxy-indole-2-carboxamide.

8. The method of claim 1 in which the compound is N-(I ethyl 2pyrrolidylmethyl)-1-butyl-3-methoxy-' dole-Z-carboxamide.

References Cited UNITED STATES PATENTS 3,198,807 8/1965 Thominet260-32614 X OTHER REFERENCES Paul et al.: J. Am. Chem. Soc.,82:4596-4600 (1960).

STANLEY J. FRIEDMAN, Primary Examiner

